Our laboratory studies the role of a transcriptional represser called B Lymphocyte Induced Maturation Protein -1 (Blimp-1). Blimp-1 controls critical cascades of gene regulation in B and T lymphocytes and is required for terminal differentiation of B cells and for development and homeostasis of T cells. Blimp-1 is also expressed in epithelial cells. We have recently created mice with a keratinocyte-specific deletion of Blimp-1 using keratin-14 Cre mice. These mice have defects in the granular layer/stratum corneum transition and formation of the stratum corneum, defects in sebocyte differentiation and sebum release and delayed hair cycle. Our long-range goal is to take advantage of this requirement for Blimp-1 in epidermis to learn more about molecular mechanisms of gene regulation that control differentiation of interfollicular keratinocytes, sebocytes and inner root sheath cells of the hair follicle. In this proposal, we will focus on the defect in the granular layer/stratum corneum transition of IFE keratinocytes in mice having a keratinocyte-specific conditional knock-out of Blimp-1 (CKO). We will perform biochemical, immunofluorescence and electron microscopic studies to thoroughly characterize the developmental defect. Then we will perform global gene expression studies on cells from control and CKO mice to identify and subsequently verify gene expression programs in granular layer cells that are regulated by Blimp-1. This work will provide the basis for subseuent studies to identify, both mechanistically and functionally, critical regulators of the granular layer/stratum corneum transition. Such information will aid in understanding diseases affecting the formation of normal stratum corneus and may provide targets for the development of drugs to modify misregulated differentiation. Dr. Calame qualifies as Category #2 in the Guidelines as an Established Investigator with no previous work in skin diseases. This P&F study will use Cores A and B.